Method of detecting portal and/or hepatic pressure and a portal hypertension monitoring system

ABSTRACT

The devices and methods generally relate to vibratable sensors for measuring ambient fluid pressure, in particular implantable sensors. The devices and methods are suited to implantation within the body to monitor physiological conditions, such as portal and/or hepatic venous blood pressure, and allow frequent, remote interrogation of venous pressure. The sensor devices are relatively small compared to conventional devices for measuring fluid pressure and can be implanted in the portohepatic venous system, whereas conventional devices are too large. The small size of the device is accomplished by using a thick sensor membrane, compared to conventional devices, and by limiting the size of additional elements of the device relative to the size of the sensor membrane. The thicker sensor member also obviates the need for multiple sensor arrays and maintains the accuracy and robustness of the sensor device. A data capture, processing, and display system provides a pressure measurement reading.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/129,912, filed Sep. 13, 2018, which claims priority to U.S. patentapplication Ser. No. 13/600,437, filed Aug. 31, 2012 now U.S. Pat. No.10,105,067, which claims the benefit of priority to U.S. ProvisionalApplication No. 61/530,040, filed on Sep. 1, 2011, all of whichapplications are incorporated herein by reference in their entirety.

FIELD OF INVENTION

The method and apparatus generally relate to measuring ambient pressurein systems comprising incompressible fluids. More precisely, the methodand apparatus relate to monitoring blood pressure, and the correspondingblood pressure gradient, between the portal and hepatic veins whichtogether comprise the porto-hepatic venous system, via a small, passive,sensor that is deployed (implanted) in the portal vein only or in boththe hepatic and portal veins. The sensor is capable of implantation inthe porto-hepatic venous system due to its reduced dimensions, ascompared to current sensors for measuring fluid pressure which are toolarge and invasive to allow frequent, accurate monitoring ofporto-hepatic blood pressures. The implanted sensor measures portal veinblood pressure and/or the porto-hepatic venous pressure gradient bycorrelation between the blood pressure and the frequency response of thesensor, and may be used in a system which provides pressure readings viaan external processing and display system.

BACKGROUND

The portal vein is a vessel in the abdominal cavity that drainsdeoxygenated blood to the liver for cleaning. A system of blood vesselscalled the hepatic veins remove the cleaned blood from the liver to theinferior vena cava, where it is returned to the heart. Portalhypertension (“PHT”) occurs when the portal vein experiences a rise inblood pressure that is not a consequence of an increase in a patient'soverall systemic blood pressure. Often, PHT is defined according to a“portal pressure gradient,” or, the difference in pressure between theportal vein and the hepatic veins, for example of 10 mmHg or greater. Atypical portal venous pressure under normal physiological conditions isless than or equal to approximately 10 mmHg, and the hepatic venouspressure gradient (HVPG) is less than approximately 5 mmHg. Increasedportal pressure leads to the formation of porto-systemic collaterals;the most serious of them being gastroesophageal varices. Once formed,varices represent a major risk for the patient due to the susceptibilityfor rupture and subsequent hemorrhage that in many cases leads to death.As a result, PHT is considered the most severe complication of cirrhosisof the liver and is the major cause of morbidity and mortality incirrhosis patients.

Current procedures for monitoring portal pressure generally involve anindirect measurement of the portal venous pressure through the hepaticvenous system. One such procedure is known as the hepatic venouspressure gradient or HVPG. HVPG is used to provide an indirectmeasurement of the portal vein pressure. The procedure is minimallyinvasive and involves catheterization of the hepatic venous system viafemoral vein or jugular entry. A balloon tipped radiolucent catheterthat is capable of measuring local blood pressure usually via a pressuretransducer is placed in the Inferior Vena Cava or a large hepatic veinsegment. Once in place the pressure is measured to provide the freehepatic venous pressure or FHVP. The FHVP is measured to quantify theexternal pressures being applied to the venous systems and to zero outthe effects of systemic pressure. The catheter is then advanced into asmall branch and a complete obstruction of flow is created (wedgeposition usually done by inflating balloon) to provide the wedgedhepatic venous pressure or WHVP. The HVPG is given by HVPG=WHVP−FHVP.While the HVPG has been shown to be a very effective diagnostic andprognostic indicator, it has been limited by the invasiveness of theprocedure and the need for standardization to provide reliable results.

Other indirect procedures include, for example, measurement of varicealpressure which employs esophago-gastric approaches to advance aninflatable balloon-catheter into the abdomen of patients via theesophagus and stomach and position the balloon, adjacent to agastroesophageal varix. The force of inflation required against the wallof the varix is used to calculate the intravariceal blood pressure. Ingeneral, non-direct portal venous pressure measurement is less precise,while still invasive and uncomfortable for a patient.

Direct measurement of the portal vein has been attempted in the past.One such procedure involves puncture catheterization, wherein aradiologist accesses the portal and/or hepatic venous systems, underfluoroscopic guidance, by puncturing the tissue of the system with aneedle or catheter from outside of the system. Using puncturecatheterization, the portal vein may be accessed via a transhepaticpuncture using either an intracostal or subxiphoid approach, wherein aneedle or catheter is inserted at a patient's 12^(th) vertebrae, betweenthe ribs, and punctures through to the portal vein. The hepatic venoussystem may be accessed via a transjugular approach, wherein a needle orcatheter is inserted into the jugular vein and advanced into the hepaticvein via the vena cava. The portal vein may also be accessed from thehepatic venous system, using an intrahepatic puncture from the hepaticto portal venous systems. Thus, in order to monitor a portal pressuregradient, two separate punctures (for the portal and hepatic veins) arerequired. Physicians are reluctant to perform frequent, direct portalvein pressure measurements, due to the invasiveness of the procedure andas a result, it is not clinically practiced.

There exists a strong clinical need for a pressure monitoring systemthat can provide accurate pressure measurements of portal and/or hepaticblood pressure while allowing the physician to monitor those pressuresnon-invasively.

Conventional devices include active electronics, sensors, and controlswhich require a power supply, or a connection to the outside world, andwhich increase the size of conventional devices thus restricting theiruse in the porto-hepatic venous system. In addition, conventionaldevices rely on components, for example sensors and/or membranes, thatare large and/or needed in plurality of sensors/membranes, in order tomaintain functionality, due, in part, to their tendency to rupture.

A need therefore exists for a pressure measurement system that is smallin size, sensitive in function, and does not require redundancy. Inaddition, a need exists for a sensor system that may be operated withoutthe need for wires or cables to transmit the pressure experienced by thesensor to an external device. The pressure measurement system should beminiature, passive, implantable and wireless to allow for non-invasive,frequent monitoring of portal venous pressure.

SUMMARY OF THE INVENTION

The present invention relates to a method and apparatus for measuringportal and/or hepatic pressures. The apparatus is a sensor device thatis miniature, passive, implantable and wireless, to allow fornon-invasive, frequent monitoring of portal venous pressure. The sensordevice is miniature to allow for safe implantation into the targetvessels. In one embodiment, the sensor device structure comprises asingle sensor unit having a sensor membrane of a thickness greater thanat least 1 micron and an overall sensor device size range of 0.1 mm-1 mmin width (w), 0.1 mm-1 mm in depth (d), and 0.1 mm-0.75 mm in height(h). The overall volume of the sensor device will preferably not exceed0.3 cubic millimeters. Other examples of volumetric ranges (in mm³) forthe sensor device are, e.g., 0.005-0.008, 0.01-0.09, or 0.1-0.3. Theapparatus is passive to allow the treating physician to monitor thepatient as often as is desired or needed. The invention is useful forinterrogating ambient conditions in systems that comprise anincompressible fluid particularly in measuring portal and/or hepaticpressures.

One object of the present invention is to provide a sensor device formeasuring ambient fluid pressure in a system comprising anincompressible fluid, e.g., a liquid. The sensor device may be a nakedvibratable sensor or a vibratable sensor housed in a cavity with orwithout a bottom film sealing the housing. In one embodiment, the sensordevice comprises a vibratable sensor having a sensor membrane, whichsensor membrane has a resonance frequency responsive to ambient fluidpressure conditions. The sensor membrane has a thickness in the range of1 micron-200 microns and forms one side of a chamber. The chamber isdefined by the sensor membrane and a plurality of walls which aresubstantially perpendicular to the sensor membrane. The chamber may besealed with a compressible gas of predefined pressure disposed therein.The chamber is sealed with a bonding layer using an anodic bondingprocess. The bonding layer may provide a means for attachment of thevibratable sensor to an anchoring device. As such, the sensor devicecomprising a naked vibratable sensor may be a hermetically sealed,substantially or partially non-solid component of any shape having asensor membrane and a chamber. Alternatively, the vibratable sensor maybe an acoustically-active solid, i.e., a sensor membrane without achamber. In either aspect, the vibratable sensor is biocompatible, i.e.,substantially non-reactive within a human body.

In another embodiment, the vibratable sensor may be disposed in a cavitydefined by a housing. In this embodiment a cover plate covers thehousing cavity such that the bonding layer faces the cover plate. A baseplate forms the foundation for the housing. The base plate may containan orifice exposing the sensor membrane of the vibratable sensor to thebodily environment to be measured. In one aspect of this embodiment, thehousing further comprises a bottom film. The bottom film may besemi-permeable or non-permeable to external fluids and/or tissues andmay enclose an incompressible fluid.

The present invention also relates to a method for measuring portaland/or hepatic pressure, wherein a sensor device has been implanted inone or both of the portal and hepatic veins, wherein each device has aresonance frequency response that is dependent upon ambient pressure andeach device has a predefined, non-overlapping resonance frequencyresponse to pressure comprising the steps of: subjecting each sensordevice to ultrasonic vibrations; receiving vibrations elicited in eachsensor device by the ultrasonic vibrations, each received vibrationincluding a vibration frequency; determining the resonance frequencyresponse of each device from each elicited vibration frequency;determining the ambient pressure surrounding each sensor device from thefrequency response of each sensor device; and in certain circumstances,determining a pressure gradient between each sensor device. Where twosensors are in close proximity to one another, the method furthercomprises distinguishing the frequency response of each sensor.

In one embodiment, a sensor device may be implanted in the portal veinthereby providing a combination of hemostatic and intra-abdominalpressure. In another embodiment, a sensor device may be implanted ineach the hepatic and portal venous systems. Implantation into the portalvein may be carried out via a transhepatic puncture using either anintracostal or subxiphoid approach, while the hepatic vein implantationmay be carried out through the transjugular approach. In this way, thesystem may provide information on the pressure gradient between thehepatic venous systems. In this latter embodiment, the system providesboth the porto-hepatic pressure gradient and the portal venous pressurein the same session. Implanting the sensor may also include the steps ofanchoring the sensor to a bodily tissue or organ, or securing the sensorto a scaffold and implanting the scaffold.

In another embodiment, a sensor device may be implanted in each of thehepatic and portal venous systems. For example, the portal implantationmay be performed by a transjugular approach and then traversing atransjugular intrahepatic portosystemic (TIPS) shunt for access to theportal system. In this embodiment the measured porto-hepatic pressuregradient may provide the physician with a method of non-invasivelymonitoring the patency of the TIPS shunt.

A further object of the invention is to provide a method for measuringportal vein pressure, with an implanted and anchored sensor device inthe portal vein comprising the steps of: applying low- andhigh-frequency acoustic waves to the sensor, receiving the frequencieselicited in the sensor by the low- and high-frequency waves, andprocessing the received frequencies as acoustic data in order todetermine the frequency response, e.g., resonance frequency, of thevibratable sensor, and thereby determine the ambient fluid pressure ofthe environment in which the sensor is disposed.

An additional object of the invention is to provide a method fordetecting and/or monitoring portal hypertension, wherein an implantedsensor device has a frequency response to ambient pressure conditionsand at least one frequency response per given pressure comprising thesteps of: transmitting low-frequency acoustic waves from a low-frequencyacoustic transmitter, transmitting high-frequency acoustic waves from ahigh-frequency acoustic transmitter, and receiving reflectedhigh-frequency acoustic waves with a high-frequency acoustic receiverand determining a pressure gradient wherein a raised pressure gradientis indicative of an active portal hypertension condition in need oftreatment. Under normal physiological conditions the gradient betweenthe portal and hepatic venous pressures is less than about 10 mm Hg. PHTis often defined as a gradient of 10 mm Hg or more. The method mayfurther comprise capturing, processing, and displaying the receivedhigh-frequency acoustic waves as acoustic data.

Another object of the invention is to provide a method for measuringambient fluid pressure in a subject system, from a sensor devicedisposed in the subject system, where the sensor device includes avibration sensor with a sensor membrane that has a resonance frequencyresponse dependent on ambient pressure conditions and at least onefrequency response per given pressure, comprising the steps of:subjecting the sensor to low- and high-frequency acoustic waves in orderto elicit acoustic resonances, or vibrations, in the sensor, detectingthe acoustic resonances as reflected signals from the sensor, andprocessing the detected acoustic resonances in order to determineambient fluid pressure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a device in accordance with the invention for measuringportal venous pressure.

FIGS. 2, 2A and 2B show a sensor in accordance with the invention formeasuring portal venous pressure.

FIG. 3 shows a system in accordance with the invention for measuring,interpreting, and displaying portal venous pressure.

FIG. 4 shows a passive sensor manufacturing method in accordance withthe invention.

FIGS. 5A-5C show various embodiments of a passive sensor anchoringdevice in accordance with the invention.

FIGS. 6A-6B show aspects of various embodiments of a passive sensorimplantation device in accordance with the invention.

FIG. 7 illustrates exemplary resonance frequencies from a vibrationsensor as a function of ambient pressure in response to three differentexcitation frequencies, based on pressure oscillations around the meanvalue to be measured.

DETAILED DESCRIPTION OF THE INVENTION

The method and apparatus of the invention generally relate to measuringambient pressure in a system comprising an incompressible fluid. Forpurposes of this application, “incompressible fluid” refers generally tonon-vapor, non-compressible, flowable media, such as liquids, slurriesand gels. In particular, the method and apparatus relate to deviceswhich are implanted in a body to monitor hepatic and/or portal venouspressure. The miniature size of the apparatus, compared to currentconventional devices for measuring ambient fluid pressure, andrelatively low invasiveness of the apparatus and method are particularlywell suited to medical and physiological applications, including, butnot limited to, measuring: i) blood vessel/artery/vein pressures suchas, for example, in portal hypertension; ii) spinal fluid pressure inbrain ventricles; iii) intra-abdominal pressures such as in the urinarytract, bladder, kidney, and bile ducts; and the like. The method may beapplicable to any disease or condition involving bodily systems throughwhich fluids, i.e., incompressible fluids, e.g., liquids, flow.

The invention is discussed and explained below with reference to theaccompanying drawings. The drawings are provided as an exemplaryunderstanding of the invention and to schematically illustrateparticular embodiments and details of the invention. The skilled artisanwill readily recognize other similar examples equally within the scopeof the invention. The drawings are not intended to limit the scope ofthe invention as defined in the appended claims.

FIG. 1 illustrates a sensor device system of the invention. Sensordevice 100 measures ambient pressure of the implanted sensor device.Sensor device 100 is subjected to high frequency acoustic waves 101 andlow frequency acoustic waves 102 which are generated by high frequencytransmitter 103 and low frequency transmitter 104, respectively. Highfrequency transmitter 103 and low frequency transmitter 104 may compriseany transducer suitable for controllably generating acoustic energybeams (such as, but not limited to sonic or ultrasonic beams) as isknown in the art. Typically such transducers are called tactiletransducers and are capable of converting an electrical signal into, forexample, vibrations that may be felt or used for work. The transducersprovide a field of view comprising a depth of penetration of 4-16 cm anda beam spot diameter of 3 cm generating a measurement ellipsoid, forexample. The transducers may be implemented using suitable piezoelectrictransducers, but other transducers known in the art may be used, suchas, but not limited to, capacitive transducers, wideband capacitivetransducers, composite piezoelectric transducers, electromagnetictransducers, various transducer array types and various suitablecombinations of such transducers configured for obtaining differentfrequencies and/or beam shapes. For example, acoustic transmittersmanufactured by Vemco, PCB Piezoelectronics, and Hardy Instruments maybe used. Acoustic waves 101, 102 are directed at the sensor device 100,producing modulated acoustic waves 105 that are detected by highfrequency receiver 106. Subsequent processing of waves 105 enablescalculation of the ambient pressure in device 100.

One aspect of the invention relates to an implantable sensor devicecomprising a miniature sensor device for measuring ambient fluidpressure. The sensor device comprises a vibratable sensor having asensor membrane, which has a frequency response to ambient pressureconditions. The sensor membrane of the vibratable sensor forms one sideof a chamber wherein resides a compressible gas of predefined pressure.The chamber is further defined by at least one wall which is preferablysubstantially perpendicular to the sensor membrane. In one embodiment,the vibratable sensor is made of silicon, but other suitable materialsmay be used, for example a metal, Pyrex® or other glass, boron nitride,or the like. Non-limiting examples of metals include, e.g., Titanium,Gold, Stainless Steel, Platinum, Tantalum, or any suitable metal, alloy,shape memory alloy such as NITINOL®. The chamber may be sealed with abonding layer forming a side of the chamber opposite the sensormembrane. Where the vibratable sensor includes a bonding layer forsealing the chamber, the bonding layer may also be used for attachmentto an anchoring means. In one embodiment, the bonding layer provides ahermetic seal for the chamber disposed in the vibratable sensor. Thebonding layer may comprise Pyrex®, glass, silicon, or other suitablematerials.

Generally, the vibratable sensor is manufactured by etching theappropriate shape and materials from a larger panel of the material. Forexample, the larger panel of material may be covered with a mask, themask defining the shape of a plurality of the desired vibratablesensors, and then subjected to etching, which may be, for example,chemical etching or physical etching. The mask protects those areas ofthe panel that must not be removed during the etching process in orderto produce the desired shape. For example, a plurality of vibratablesensors is formed when a mask having a plurality of precisely measuredcut-outs cover a larger panel of material during the etching process,until chambers of the desired shape are produced in the larger panel toa depth that is substantially equal to a cut-out in the mask. The depthof the chamber may be controlled by various factors, for example wherechemical etching is used: the volatility, duration, and number ofchemical treatments. Each vibratable sensor may then be cut from thelarger panel by slicing between consecutive chambers such that theamount of material remaining on each side of the chamber will be thethickness of walls defining a chamber in the vibratable sensor. Theamount of material remaining between the bottom surface of the chamberand bottom of the larger panel will be the thickness of the sensormembrane. Any material that requires joining may be connected, forexample, by brazing or welding.

As noted above, the vibratable sensor may additionally include a bondinglayer of, for example, Pyrex® or other suitable material, in order tohermetically seal the vibratable sensor, preferably by joining thebonding layer to the walls of the chamber such that the bonding layerand sensor membrane are substantially parallel. In one embodiment, thebonding layer and sensor membrane form opposite walls of a vibratablesensor chamber. The bonding layer may provide a surface for attachmentto anchors or other components.

FIG. 2 shows a cross sectional illustration of one embodiment of thesensor device 200. In this embodiment, the sensor device 200 is asubstantially cubic vibratable sensor 201. As such, the sensor device200 of FIG. 2 comprises a sensor membrane 209 and chamber 210 which issealed by bonding layer 211, as described above. The sensor membrane 209is comparatively thick relative to other remotely operated vibratablefluid pressure sensors. The sensor membrane 209 has a thickness in therange of 1 micron-200 microns. Some exemplary but non-limitingthicknesses include 1.5 microns, 2 microns, 2.5 microns, and 5 microns.The sensor device 200 of the invention retains its accuracy despite thecomparatively thick sensor membrane 209. The use of a single sensor (ascompared to the plurality of sensors required by prior artremotely-operated vibratable sensors) reduces the overall size of sensordevice 200 compared to such conventional devices, making sensor device200 suitable for use in the porto-hepatic venous system.

The vibratable sensor 201 has a height h, width w, and depth d. In oneembodiment, the vibratable sensor 201 measures 0.3 mm (h)×0.5 mm (w)×0.5mm (d). The width and depth of the vibratable sensor may be equalresulting in a substantially cubic structure. However, the dimensions ofthe vibratable sensor 201 may generally be any dimensions that do notexceed a maximum volume of about 0.3 mm³, preferably having a size ofequal to or less than 0.125 mm³. A minimum volume for the vibratablesensor 201 is about 0.008 mm³. Various alternative embodiments of thevibratable sensor 201 have volumetric ranges (in mm³) of, e.g.,0.005-0.008, 0.01-0.09, or 0.1-0.3, as use requires. Vibratable sensor201 may be solid, or may be a hermetically sealed, substantiallynon-solid component, of any shape, which includes sensor membrane 209and chamber 210, in the example illustrated by FIG. 2 . Sensor membrane209 in the illustrated example is a side of the chamber 210 of thevibratable sensor 201. The depth of the chamber 210 is defined by theheight (h) of the walls 203 of the vibratable sensor 201. The sensormembrane 209 may have a thickness (t) on the order of about 2 microns inthickness (t), but more generally, the thickness (t) of the sensormembrane 209 is greater than one micron and less than or equal to 200microns. Thickness (t) is measured along the height dimension (h) asdepicted in FIG. 2 .

Vibratable sensor 201 may comprise the cropped rectangular overall shapeillustrated in FIG. 2 , or one or more other suitable shapes, includingbut not limited to a sphere, pyramid, trapezoid, or other symmetrical ornon-symmetrical shape. In one embodiment, the vibratable sensor 201comprises silicon. In another embodiment vibratable sensor 201 comprisestitanium or another acoustically active material. In other embodiments,vibratable sensor 201 comprises a rubber, polymer, and/or a ceramicmaterial. Alternatively, the vibratable sensor 201 may comprise anysuitable material capable of being excited by acoustic stimulation. Asused in this application, “silicon” refers to silica and silicates,glasses, cements, and ceramics; it also refers to the class of siliconesfor which it is a constituent element, including various syntheticplastic and rubber substances made of silicon, oxygen, carbon andhydrogen, for example.

In other embodiments of the sensor device 200, illustrated in FIGS. 2Aand 2B, the vibratable sensor is disposed in a cavity 208 defined by ahousing 202. The housing 202 encloses the sides of the vibratable sensor201 but not all or part of the sensor membrane (209 in FIGS. 2 and 2B,unnumbered in FIG. 2A), and the bonding layer 211 faces a cover plate204 which is mechanically fixed to one side of the housing and serves asa surface for attachment to an anchoring means in certain embodiments.In one aspect of the embodiment illustrated in FIG. 2A, the cover plate204 may include a fill port 205. The fill port 205 may be used to fillthe cavity 208 with an incompressible fluid. As illustrated in FIGS. 2Aand 2B, the housing 202 is disposed atop a base plate 206, whichprovides a foundation for the housing 202 and holds the vibratablesensor 201 inside the cavity 208. The base plate 206 may contain anorifice 212, as shown in FIG. 2B, which exposes the sensor membrane 209to acoustic activity thereby allowing vibrations to reach and returnfrom vibratable sensor 201.

In the particular embodiment illustrated in cross-sectional view in FIG.2B the vibratable sensor 201 is disposed in cavity 208 of housing 202,wherein the orifice 212 in base plate 206 exposes all or a portion ofthe sensor membrane 209 of vibratable sensor 201 to an acousticallytransparent bottom film 207. Bottom film 207 is designed to allow forthe transmission of acoustic waves, hydrostatic and hydrodynamicpressures from the surrounding environment. Depending upon the choice ofmaterial used for the bottom film 207, it may also function to protectthe sensor. When the bottom film 207 comprises a semi permeablematerial, the film protects the vibratable sensor from direct exposureto bodily tissues or other solid bodily matter. When the bottom film 207comprises an impermeable material, the film 207 may completely protectthe vibratable sensor from all bodily fluids and/or materials. In anembodiment wherein the bottom film 207 is impermeable to all fluids andsolids, a fill port (not shown in FIG. 2B) may be used to fill thecavity 208 with an incompressible fluid. Bottom film 207 comprises anysuitable bioinert material or combinations thereof, including but notlimited to, titanium, gold, stainless steel, platinum, tantalum, or anysuitable metal, alloy, shape memory alloy such as NITINOL®, silicon,glass, quartz, a ceramic material, a composite material, a metallic ornon-metallic nitride, boron nitride, a carbide, a metal oxide, anon-metallic oxide, a polymer based material, a gel, and combinationsthereof. Alternatively, bottom film 207 may comprise titanium in oneembodiment, for example diffusion-bonded Grade I titanium. In variousembodiments, bottom film 207 may substantially seal vibratable sensor201 in cavity 208, for example when bottom film 207 comprises asubstantially non-porous material, or bottom film 207 may be porous, tovarying degrees, and expose vibratable sensor 201 to bodily fluidsand/or tissues. In the embodiment shown in FIG. 2A, described above,bottom film 207 is absent from base plate 206. In such an embodiment,the vibratable sensor 201 would be completely exposed to the ambientenvironment via orifice 212.

Cover plate 204, housing 202, and base plate 206 may each comprise anysuitable bioinert materials or combinations thereof, including but notlimited to titanium, gold, stainless steel, platinum, tantalum, or anysuitable metal, alloy, shape memory alloy such as NITINOL®, silicon,glass, quartz, a ceramic material, a composite material, a metallic ornon-metallic nitride, boron nitride, a carbide, a metal oxide, anon-metallic oxide, a polymer based material, a gel, and combinationsthereof. Alternatively, base plate 206 may comprise a Pyrex® material.Base plate 206, housing 202, and cover plate 204 comprise titanium inone embodiment, for example Grade I titanium. These components may beformed and assembled from separate pieces or may be formed as oneelement or combined elements to function as described above.

In the embodiment depicted by FIG. 2B, the vibratable sensor 201contained in the housing cavity 208 may be surrounded by bodily fluid,e.g., blood-flow, which enters the cavity 208 via a porous or absentbottom film 207. Alternatively, the vibratable sensor 201 may besurrounded by an incompressible fluid that is sealed in cavity 208 by asubstantially solid or impermeable bottom film 207, after theincompressible fluid is introduced to cavity 208 through fill port 205.A substantially solid bottom film 207 also prevents the introduction ofbodily fluids and/or tissues into cavity 208.

Base plate 206 is relatively thin (in the h direction), generally,compared to the overall height of the device as shown in FIGS. 2A, 2B.In one embodiment, base plate 206 represents, for example, 100 micronsof an approximately 500 micron overall device height. In otherembodiments, base plate 206 may be 5%-20% of the overall device height,but is generally less than or equal to 40% of the overall device height.The height of the base plate 206 should generally be minimized to allowfor a maximum cavity 208 volume, which contributes to the accuracy ofthe device and therefore an overall reduced size when compared toconventional, vibratable sensors having a housing. The base plate 206also provides a foundation for the device assembly, and absorbsmechanical stresses by providing a sink material (a material to absorbforce or energy) where such stresses may dissipate.

Bottom film 207 may be bonded to all or a portion of the base plate 206and provides further tolerance for stresses. The relatively thin bottomfilm is generally on the order of 1-10 microns. In one embodiment, thebottom film 207 is desirably 4 microns in thickness. The thin bottomfilm 207 is generally more pliable than thicker components of the deviceand may absorb stresses from, for example, expansion and contraction dueto changing temperatures. Bottom film 207 is designed to allow for thetransmission of acoustic waves, hydrostatic and hydrodynamic pressuresfrom the surrounding environment.

As illustrated in FIG. 2B, cover plate 204 is substantially parallel tobase plate 206, and base plate 206 is substantially parallel to, anddisposed on, bottom film 207. FIG. 2B shows a cross-section of thesensor having a wafer-style stacking of the bottom film 207, base plate206, vibratable sensor 201, housing 202, and cover plate 204, whereinthe layers may be hermetically sealed and the vibratable sensor 201 isdisposed in the cavity 208 of the housing 202 in the illustratedembodiment. Techniques for hermetically sealing the layers of the sensorinclude but are not limited to diffusion bonding. In certainembodiments, bottom film 207 is sealed by controlled environment methodsthat minimize oxygenation and other impurities of the bottom film, whereconventional, uncontrolled sealing techniques may damage the bottomlayer 207. Remaining volume within the cavity 208 may be filled with anincompressible fluid, through the fill port 205 (FIG. 2A) of the coverplate 204. After filling is complete, fill port 205 is temporarily orpermanently sealed with different welding technologies such as, forexample, arc, laser, resistance, ultrasonic, or torsional, or bydiffusion bonding, swedging, adhesives gaskets, capillary seals, orother suitable means for sealing. The manufacturing and assembly methodis detailed herein below with respect to the description of FIG. 4 .

The overall size of the sensor device 200 depicted in FIG. 2 , which isdesirably extremely small compared to conventional wireless devices formeasuring fluid pressure, may be 0.1 mm-1 mm in width (w), 0.1 mm-1 mmin depth (d), and 0.1 mm-0.75 mm in height (h). In one embodiment, thesensor device 200 has an equal width and depth, forming a substantiallycubic structure. Generally, the overall volume of the sensor device willnot exceed 0.3 cubic millimeters. For the embodiment shown in FIGS. 2A,2B, housing 202 has a minimum wall thickness of 300 microns. Base plate206 has a height, h of approximately 100 microns. Further, base plate206 is relatively thin compared to the overall height of the sensordevice 200 depicted in FIGS. 2A, 2B, which may be, for example, 100microns (base plate 206) compared to 500 microns (for the overall sensordevice). Such a configuration provides more robustness for sensor device200. In addition, cavity 208 desirably has a height of approximately 400microns—measured from the surface of base plate 206 abutting cavity 208to the surface of cover plate 204 abutting cavity 208—but is at least100 microns in height, and is relatively large compared to the overallheight of the device, 400 microns (cavity) versus 500 microns (height ofthe overall sensor device) in the example of FIGS. 2A, 2B.

The above principles allow for an overall reduction in size fromconventional wireless devices for measuring fluid pressure, because theabove principles allow for a relatively thick (greater than 1 micron,for example, 2 microns) sensor membrane 209 which is accurate and robustenough to obviate further active components and/or sensor arrays.

Another aspect of the invention relates to a method for determiningpressure in the porto-hepatic venous system. Once the sensor device 100(FIG. 1 ) is located, data is collected using the transmitter/receiverarray 103, 104, 106 as illustrated in FIG. 1 . High frequency 101 andlow frequency 102 acoustic beams are generated by high frequency 103 andlow frequency 104 transmitters, and applied to sensor device 100.Acoustic beams 101, 102 are typically initiated by positioning thetransmitters 103, 104 in close but external proximity to the sensordevice 100, where “close proximity” is any distance sufficient to applyacoustic beams 101, 102 to sensor device 100 in accordance with thedevices and methods herein. Vibrations from the sensor, interrogated andexcited by the high frequency 101 and low frequency 102 acoustic beams,create modulated acoustic waves 105, due to the vibration of thevibratable sensor 201 (FIG. 2 ). Modulated acoustic waves 105 aredetected by high frequency receiver 106 which is also placed in closeproximity to sensor device 100.

FIG. 3 shows one embodiment of a processing and display system 300 ofthe system of the current invention and illustrates operation of thesensor device in the system. FIG. 3 makes reference to FIG. 1 , whichillustrates a generic sensor device 100 of the system of the invention,however the processing and display system 300 of FIG. 3 applies equallyto the sensor device 200 as illustrated in FIGS. 2, 2A and 2B. Thus, forpurposes of describing the operation of the sensor device and systemwith reference to FIG. 3 , sensor device reference numbers 100 and 200are used interchangeably.

Referring to FIG. 3 , high frequency receiver 106 transmits data 305 toprocessing unit 301. Data 305 may include radio waves, electricalsignals, digital signals, waveform signals, or any other meanssufficient for communicating the acoustic properties of modulatedacoustic waves 105, as received by high frequency receiver 106.Processing unit 301 interprets data 305 using the properties ofmodulated acoustic waves 105 to determine a frequency response of thesensor device 100. The frequency response of the sensor is definedherein as the frequency of vibrations, including at least one resonancefrequency, emitted by the sensor in response to the transmission ofultrasonic vibrations from transmitters 103, 104, at a given ambientpressure. For example, the frequency response of sensor device 100 isknown when sensor device 100 is subject to “normal”, i.e.,non-symptomatic, physiological conditions. In the portal venous system,“normal” conditions are a pressure approximately 5 mmHg or less, and apressure gradient between the portal and the hepatic vein ofapproximately 10 mmHg or less. The internal pressure of sensor device100—i.e., the pressure within cavity 208—is known and substantiallyconstant. In the portal venous system, the frequency response of sensordevice 100 changes in accordance with changes in the venous pressure.Low-frequency acoustic waves 102, for example at 50 kHz, will stimulateat least one frequency response of vibrations in sensor device 100, at agiven pressure, by exciting vibrations in vibratable sensor 201 (FIG. 2). High frequency acoustic waves, for example 750 kHz, may be used tointerrogate the excited vibratable sensor 201 (FIG. 2 ). This results inmodulated acoustic waves 105 that can be detected by receiver 106. Highfrequency acoustic waves are meant to interrogate, not to excite, themembrane 209 of the vibratable sensor 201, and preferably minimallyinteract with the membrane 209 to maximize linearity of the system.

One type of frequency response which may be measured according to thepresent invention is a resonance frequency. For example, resonancefrequency(-ies) of the sensor device 100 may be identified as thefrequency(-ies) which exhibit peak vibration amplitudes returned fromthe sensor device 100. In an alternative embodiment, the resonancefrequencies are absorbed by bottom film 207, and therefore do notmaterialize as vibrations generated by the sensor device 100, and areidentified as the frequencies where vibrations are not returned from thesensor device 100, or where the minima of amplitude vibrations returnedfrom sensor device 100 exist. The difference between the actualresonance frequency excited in the sensor device 100 and the resonancefrequency of the sensor device under normal conditions is correlated tothe difference in pressure between normal conditions and the actualblood pressure. Thus, actual portal venous pressure is calculated basedon the measured resonance frequencies of sensor device 100.

In one embodiment of the invention, the low frequency transmitter is anannular low frequency piezoelectric transducer having a working range of0-100 kHz, 30-100 kHz, or 50-100 kHz, for example, depending on theprecision required. It is, however, noted that any other suitable lowfrequency transducer known in the art may be used for implementing theinvention.

In another embodiment of the invention, the high frequency transmitter103 is an annular high frequency transmitting transducer, implemented asa low noise (i.e., low-range or low-bandwidth) frequency generator unitdesigned to generate a high frequency acoustic wave 101 at, for example,750 kHz. It is noted, however, that other different values of the highfrequency acoustic wave may also be used in implementing the presentinvention.

In one embodiment of the invention high frequency receiver 106 is adisc-like high frequency receiving piezoelectric transducer. The annularhigh frequency transmitter 103 and the high frequency receiver 106 are,for example, a model CLI 7900 general-purpose ultrasonic probe,commercially available from, for example, Capistrano Labs, Inc., SanClemente, Calif., USA. When the acoustic waves including the highfrequency acoustic waves 101 and low frequency acoustic waves 102 aredirected at the sensor device 100, the high frequency receiver 106receives the modulated acoustic waves 105 which are excited in thesensor device 100 as well as other noise, e.g., signals that arereflected from other materials in the measurement environment orinterference. The high frequency receiver 106 generates an electricalsignal representative of the returning acoustic signals that itreceives. The electrical signal produced by the receiver 106 isprocessed by the system described herein, for example as shown in FIG. 3.

In another embodiment, low frequency transmitter 104 has a working rangeof 30-90 kHz, and transmits acoustic frequencies, for example, at 50kHz; high frequency transmitter 103 transmits, for example, atapproximately 750 kHz with a narrow bandwidth (range); high frequencyreceiver 106, under the example, operates in the range of 750 (high)±50(low) kHz. Low frequency transmitter 104, high frequency transmitter103, and high frequency receiver 106 may alternatively operate in anyrange suitable for use with the devices and methods disclosed herein,and as particularly required for measuring fluid pressure in particularenvironments.

High frequency receiver 106 is also a transducer, and is used forreceiving the signals returning from the sensor when the sensor isinterrogated by the high frequency acoustic waves 101. For example, thetransducer may be implemented using suitable piezoelectric transducers,but any other type of transducers known in the art may be used toimplement the transducers, such as, but not limited to, capacitivetransducers, wideband capacitive transducers, composite piezoelectrictransducers, electromagnetic transducers, various transducer arraytypes, cMUTs, cymbal transducers and various suitable combinations ofsuch transducers configured for obtaining different frequencies and/orbeam shapes. For example, acoustic receivers manufactured by Vemco, PCBPiezoelectronics, and Hardy Instruments may be used.

Modulated acoustic waves 105 are the result of combining high frequencyacoustic waves 101 and low frequency acoustic waves 102 in a reversiblemanner, in order to achieve a waveform with a desired frequency,wavelength, and/or amplitude. Unmodulated noise, for example caused byreflections of acoustic waves off of materials in the sensor device 100environment, is thus distinguished from the modulated acoustic waves 105that are excited by the sensor device 100. When the received signalamplitude (in dB) is analyzed according to the frequency (in MHz), theamplitude peaks at the resonance frequency of the sensor device 100.High frequency receiver 106 communicates the modulated acoustic waves105 to a processing and display system, detailed in FIG. 3 , forinterpretation and use.

In one embodiment, vibrations excited in sensor device 100 aredistinguished from noise by correlating pressure measurements to a heartrate or pulse measurement. In this embodiment, a plurality of pressuremeasurements are taken during the interrogation period, for example, atleast one cycle of expansion and contraction of the heart (pulse cycle).During the pulse cycle, the pressure of the entire vascular system willchange continuously as the heart draws blood in and forces blood out.Accordingly, an acoustic signal that changes in a consistent mannercorrelated to the pulse cycle demonstrates an excitation in the sensor.Noise reflected from, for example, surrounding tissues in theinterrogation environment, does not produce such a continuously changingsignal that is correlated to the pulse cycle. The above features are notlimited to a single embodiment; rather, those features and functions maybe applied in place of or in conjunction with the other embodiments andconcepts herein. The pulse cycle and waveform may be measured by anexternal device, for example using a pulse oximeter, heart rate monitor,ECG, etc. Optionally, such instruments may be connected to the pressuremonitoring system of the invention to input the pulse or pulse waveforminto the system for correlation with the acquired pressure waveform fromthe sensor to determine the validity of the acquired signal.

In operation, sensor device 100 is disposed in a measurementenvironment, for example, implanted in an area, vessel, artery, or thelike, where pressure measurements are desired. The sensor system may beimplanted by methods including, for example, portal venouscatheterization procedures to position the sensor device 500 in theportal vein shown, for example, via scaffoldings 504 illustrated inFIGS. 5A-5C and FIGS. 6A-6B. In such a procedure a percutaneoustranshepatic approach to the portal vein may be employed, for exampleinserting the cannula 601 into a subject between the ribs and puncturingthrough to the portal vein. For the hepatic vein, the sensor device 500may be inserted, for example, by transjugular hepatic vein access,similar to the procedure used in hepatic vein pressure-gradientmeasurements. In this procedure, a catheter is inserted into the jugularvein in the neck and advanced into the hepatic vein via the vena cava.The portal vein is also accessible by puncture from the hepatic vein,after a catheter has been inserted via transjugular hepatic proceduressimilar to the implantation of transjugular intrahepatic portosystemicshunts. Implantation into the portal vein may also involve traversing aTIPS shunt, in which case the patency of the TIPS shunt may benon-invasively monitored. Implantation is typically performed by aninterventional radiologist under fluoroscopic guidance. Sensor device500 is guided to the intended position using catheter delivery system600, for example, as shown in FIGS. 6A-6B. Once deployed in the intendedlocation, sensor device 500 remains in the vessel or area. Other methodsfor deploying the sensor as are known in the art may alternatively beemployed. Non-limiting examples of such deployment methods include, butare not limited to, those described in U.S. Pat. No. 6,331,163 to Kaplanand U.S. Patent Publication No. 2005-0124896 to Richter, which areincorporated herein by reference.

According to one aspect of the invention, the implanted sensor device100 is subjected to both high and low frequency acoustic waves 101, 102,the latter excites vibrations in the sensor device 100, and thereflected high frequency acoustic waves are then manifested as modulatedacoustic waves 105. High frequency receiver 106 receives the modulatedacoustic waves 105 and communicates the properties of the modulatedacoustic waves 105 to a processing and display system, detailed in FIG.3 , for interpretation and use.

Returning to FIG. 3 which shows one embodiment of a processing anddisplay system 300 of the current invention, data 305 from highfrequency receiver 106 is transmitted to a processing unit 301 whichdetermines the pressure of the environment surrounding the sensor device100. Data 305 is communicated between high frequency receiver 106 andprocessing unit 301 via a wired 308 or wireless 309 connection. Wiredconnection 308 is, for example, an electronic cable or integralconnection, or the like. Wireless connection 309, for example, operatesby transmitting radio waves, acoustic waves, or other known media forremotely communicating data.

Processing unit 301 may comprise a computer, workstation, or otherelectrical or mechanical device programmed to perform the dataconversions and/or displays described herein and as needed for themethod of use. By way of a non-limiting example, the invention may bepracticed on a standard workstation personal computer, for example thosemanufactured by Dell, IBM, Hewlett-Packard, or the like, and whichtypically include at least one processor, for example those manufacturedby Intel, AMD, Texas Instruments, or the like. Processing unit 301 alsocomprises dedicated hardware and/or software, e.g., a data capturesystem such as the National Instruments PCI-6115 data capture board ormay be comprised of a custom designed device for that purpose.

The output of processing unit 301 is a pressure measurement that isconverted to a usable, displayable measurement either by processing unit301 or display unit 302, or a combination thereof. For example, pressuremeasurements may be reported in numerical units of mmHg or Torr or maybedisplayed with relation to a predefined arbitrary scale. Display unit302 may comprise a monitor, numerical display, LCD, or other audio orvisual device capable of displaying a numerical measurement. As shown inthe embodiment of FIG. 3 , display unit 302 is connected to or integralwith processing unit 301 by connection 306, for example in the case of acomputer with processing and display units, which optionally includes asa remote element, separate wired element, or integral element toprocessing 301 and/or display 302 units, interface 303 and input/outputelements 304, such as a keyboard, mouse, disk drive, optical pen, or thelike, to allow a user to collect, manipulate, track, and record data.Connection 306 may optionally be a remote connection 307, operating bytransmission of radio waves, acoustic waves, or other known remotetransmission methods.

One aspect of the invention is directed to a method of monitoring PHT.The sensor device 100 may be implanted in either or both of the portaland/or hepatic veins according to the procedures described herein orknown. Once implanted in the porto-hepatic venous system, the methodcomprises the steps of: subjecting the sensor device 100 to ultrasonicvibrations from high frequency 103 and low frequency 104 transmitters;receiving the frequency response of one (or each) of the sensor devices100; determining a resonance frequency of the (or each) sensor device100 from the received frequency response; determining ambient fluidpressure surrounding the (or each) sensor device 100 from the resonancefrequency of the (or each) sensor device 100; determining a pressuregradient between each sensor device 100 (in each of the portal andhepatic veins) wherein an elevated gradient (generally greater than 10mm Hg) is indicative of an active portal hypertension condition in needof treatment; and displaying and/or recording the pressure measurementsaccording to the system described with respect to FIG. 3 . Thus, thepressure of the portal and/or hepatic veins may be independentlyinterrogated, determined, and displayed. Where the pressure gradientbetween the portal and hepatic veins is desired, one sensor may beimplanted in each of those systems, and data captured for each sensor inthe manner described above. The numerical measurement of the hepaticvein pressure, for example, could then be subtracted by furtherprocessing from the numerical measurement of the portal vein pressure,providing the gradient, or difference in pressure, between the twosystems.

The method of monitoring a pressure gradient between the portal andhepatic veins includes the additional step of delineating between eachsensor while performing the interrogation. The mechanism for thedifferentiation can be one of the following or both: (i) differences infrequency responses between the sensors may be detected by changing thedimensions of the membrane while maintaining the pressure ranges andaccuracy of the sensor (i.e., one sensor will have a frequency responseat a defined pressure between 30-50 kHz while the other may have afrequency response of 60-80 kHz at the defined pressure). Such a designentails a low frequency transmitter with a wide enough bandwidth toenable the operation of both sensors (i.e., between 30-50 and 60-80kHz), or two or more low-frequency transmitters, one for each type ofsensor; (ii) a narrow high or low (or both) frequency acoustic field isapplied to the vicinity of the sensors to precisely locate each sensorduring interrogation while acoustically isolating any other sensors inthe vicinity.

In one embodiment, determining the pressure in the portal and/or hepaticveins comprises obtaining the mean pressure by a phase inversion methodof calculation, which relies on small pressure oscillations created bythe heartbeat. The small pressure oscillations exist around the meanpressure value which is to be measured. In order to determine the meanpressure value to be measured, a receiver as described for example withrespect to FIG. 3 measures the response power of the sensor device,which is the amplitude of the oscillation of the vibratable sensor andis measured in decibels (dB). As illustrated in FIG. 7 , the smallpressure oscillations occur around a particular mean value—for example90 Torr, indicated by the solid vertical line. When the sensor device isexcited by certain frequencies, for example f1 and f2, the responsepower is an increasing function of the pressure, whereas excitation byanother frequency, f3, results in a response power that is a decreasingfunction of the pressure. As a direct result the response power of f1and f2 oscillate in phase with each other (and with the pressure) andthat of f3 oscillates with an opposite phase. When the small pressureoscillations occur around a different mean value—for example 100 torr,indicated in FIG. 7 by the dashed vertical line—the response power of f1is an increasing function of the pressure, whereas that of f2 and f3 aredecreasing functions of the pressure. As a result, the response power off1 oscillates in phase with the pressure, and that of f2 and f3oscillated with an opposite phase. The phase inversion algorithm isbased on these observations. The resonance frequency of the sensordevice at the mean ambient pressure is that around which the phaseinversion occurs. In this embodiment, the pulse cycle and waveform maybe measured with an external device for correlation with the acquiredpressure waveform from the sensor.

This technique is particularly applicable to PHT since only a meanpressure reading is necessary.

With reference now to FIG. 4 , one example of a manufacturing methodembodiment is shown for a sensor device in accordance with the devicesand methods described herein. In step 401, vibratable sensors are etchedand cut from a panel of material to produce a plurality of individualvibratable sensors 402, each of which may be hermetically sealed with alayer, such as bonding layer 211 (illustrated in FIGS. 2, 2B) made of,for example, Pyrex®, which may be anodically bonded to one side ofvibratable sensor 402, or attached by brazing, welding (such as, forexample, arc, laser, resistance, ultrasonic, or torsional), diffusionbonding, vapor deposition, adhesives, epoxies, or the like. Eachvibratable sensor may then be assembled into a sensor device directly ormay be further processed to be inserted into a housing cavity, asdescribed below. Housing defining a cavity may be created in parallelsteps, in which an individual housing is etched and cut 403 from largerpanels of material and assembled 404 into a housing having a cavity.Cutting is accomplished by any suitable method, e.g., chemical etching,laser cutting, mechanical cutting, plasma cutting, punching, or thelike. In a similar fashion if a cover plate is desired, a cover plateand fill port are machined 405 from a larger panel of material.Similarly, a base plate may be machined 406 from a larger panel ofmaterial. In one embodiment, a bottom film is hermetically sealed to theface of the base plate opposite the face that will abut the stackedassembly, in step 407, via brazing, welding (such as, for example, arc,laser, resistance, ultrasonic, or torsional), diffusion bonding, vapordeposition, adhesives, epoxies, or the like. In another embodiment, thebottom film is not used. A vibratable sensor is then inserted into thecavity in the housing and the sensor-housing assembly is disposed on abase plate in a wafer-style stacking arrangement 408 (see also FIG. 2B).As part of step 408, the cover plate is disposed on the housing andencloses the vibratable sensor in the cavity, and the base plate andhousing, and housing and cover plate, are hermetically sealed viabrazing, welding (such as, for example, arc, laser, resistance,ultrasonic, or torsional), diffusion bonding, vapor deposition,adhesives, epoxies, or the like. In a further, non-illustrated step, theempty space of the cavity surrounding the vibratable sensor is filledwith an incompressible fluid via the fill port in the cover plate, andthe fill port is subsequently hermetically sealed using brazing, welding(such as, for example, arc, laser, resistance, ultrasonic, ortorsional), diffusion bonding, or the like.

In the embodiment where the sensor without a housing is desired, thesensor is further manufactured by attaching the vibratable sensor to ananchoring means. In one embodiment, a bonding layer (illustrated as 211in FIGS. 2, 2B) is attached to the vibratable sensor by brazing,welding, diffusion bonding, vapor deposition, adhesives, epoxies, or thelike. The bonding layer provides a surface to attach the sensor to asupport structure, for example an anchoring means. The bonding layer andsupport structure may be joined by brazing, welding, diffusion bonding,vapor deposition, adhesives, epoxies, or the like. In one embodiment,the bonding layer comprises Pyrex®.

The sensor device with or without a housing may be fixed to a desiredsupport structure by various means known in the art. A support structuresuch as, for example, an annular shaped structure may be pressed againstthe vessel wall wherein the sensor device is attached thereto. Inanother embodiment, hooks, tethers, or other fixation devices may beused to fix the sensor into the desired position. FIG. 5A showsattachment of sensor device 500 to an exemplary anchoring means; in thisexample, sensor device 500 may be diffusion bonded, welded, brazed,soldered, or otherwise suitably attached to an inner side 505 ofscaffold 504. Scaffold 504 may be a stent-like structure, which is atubular device that is typically implanted in a damaged vessel or arteryto maintain the opening of the vessel or artery, as described forexample in U.S. Pat. No. 7,763,064 to Pinchasik. Scaffold 504 comprisesinner side 505, an outer side 506, and a longitudinal axis 507. In someembodiments, scaffold 504 has a high degree of radial force in directionr, in order to hold a vessel or artery open. When a stent is used asscaffold 504 it is preferred that the stent provide sufficient radialresistance in direction r (see FIG. 5B) to hold the stent in a constantposition in the vessel; i.e., to secure the sensor in the desiredposition. U.S. Pat. No. 7,763,064 to Pinchasik describes such scaffoldsand is incorporated by reference in its entirety.

The scaffold 504 may be either self-expanding or expanded by aninflatable balloon. In one embodiment the scaffold is balloonexpandable, and the delivery system includes an inflation lumen. Aninflation balloon may be coaxially disposed on the outside of thecannula or catheter. Scaffold 504, including passive sensor 500, iscrimped onto the inflation balloon for insertion and placement. Afterscaffold 504 is in place within the body, inflation balloon is inflatedunder the control of the operator. Scaffold 504 expands until it reachesa desired diameter within a vessel or area. The inflation balloon isthen deflated and removed, leaving scaffold 504, including sensor device500, within the vessel or area. Scaffold 504 comprises, for example,nitinol, stainless steel, cobalt chromium, or other biocompatiblematerials with sufficient elasticity and plasticity to expand under theforce of inflation balloon and remain securely in place after expansion.

In another embodiment, scaffold 504 is made from Nitinol, or anotherself-expandable material that will expand, for example, under higher, invivo, temperatures and pressures. For certain sensor devices, it may bedesirable to deploy the sensor without the need for an inflation balloonto prevent damage to the attached sensor device. U.S. 2006/0122691 toRichter, for example, discusses such materials and their use inscaffolds and is incorporated by reference in its entirety.

Scaffold 504 comprises, for example, nitinol, stainless steel, cobaltchromium, or other biocompatible materials with sufficient elasticityand plasticity to expand under the force of inflation balloon inflatingand remain securely in place after expansion. Typically, an animal bodywill respond to the presence of a foreign object, such as the scaffold504, by forming neointima, which aids in securing the scaffold 504. U.S.patent publication no. 2006/0122691 to Richter, for example, discussesneointimal growth and securing scaffolds in place by burying thescaffold in neointima and is incorporated by reference in its entirety.

FIG. 5B shows an embodiment where sensor device 500 is tethered toscaffold 504 via a lead line 509, which is a stent strut, cable, wire,or other suitable material that is capable of resisting the force ofblood-flow and potential influence on the position of the device, and isbioinert as herein discussed. A lead line is attached to sensor device500 and scaffold 504 by welding, brazing, tying, adhesives, or the like,or may be an integral part of scaffold 504.

An alternative method of implanting a sensor device of the invention ina measurement environment involves the use of an anchoring mechanismother than a scaffold. FIG. 5C illustrates an embodiment for ananchoring mechanism from the prior art comprising a first support leg590 and a second support leg 591 which are attached at a first end 595to the sensor housing 592 of a sensor device of the invention. At asecond end 593, each support leg 590, 591 has a protrusion 594 in theshape of a hook, or the like. The protrusions 594 of the anchoringmechanisms attach to the tissues or walls of vessels in which the sensorhousing 592 is implanted, thereby securing the assembly.

The sensor of the invention may be delivered to the target site byvarious methods known in the art. Implantation into the portal vein maybe done via a transhepatic puncture using either an intracostal orsubxiphoid approach. Implantation may also be done using a transjugularapproach that would necessitate an intrahepatic puncture from thehepatic to portal venous systems. FIGS. 6A and 6B show one embodiment ofa delivery system 600 for use in delivering the sensor device 500 andattachment means to the sensing environment. As illustrated in FIGS. 6Aand 6B, the delivery system 600 comprises an intravenous cannula orcatheter that includes an internal tube 604 having a lumen about alongitudinal axis 605 and an external or outer tube 611. A cut-away viewof 611 in FIGS. 6A and 6B shows the scaffold 504 with the sensor 500 maybe coaxially disposed about the internal tubular structure 604 of thedelivery system, for example a cannula or catheter. In this embodiment,the scaffold 504 is self-expanding. As shown in FIGS. 6A and 6B, thescaffold 504 may be crimped around the internal tube 604 and held in thecompressed delivery configuration by the outer tube 611. To deploy thescaffold 504, the outer tube 611 is removed to permit the scaffold 504to expand and engage the vessel lumen. Once expanded the interior tube604 may be withdrawn leaving the scaffold 504 in the vessel, with thesensor 500 exposed to the ambient fluid of the vessel. In the embodimentillustrated in FIGS. 6A-6B, the cannula 604 or catheter has at a distalend 601 a trocar 602 having a sharp tip 609 for puncturing the bodilytissues and organs is coaxially disposed inside the lumen of the cannula601. Alternatively the cannula 604 or catheter on which the scaffold 504is disposed may be threaded through a needle-based system, which is usedto penetrate the tissue and into the appropriate vessel, and advanced tothe location where the sensor device 500 is to be deployed. Preferably,the tip of the catheter has a soft, rounded tip.

FIG. 6A shows an embodiment, wherein the scaffold 504 and sensor device500 depicted in FIG. 5A are mounted on the catheter delivery system 600coaxially. FIG. 6B shows a similar delivery system for a sensor 500attached to scaffold 504 by lead line 509. When the scaffold 504 isimplanted and expanded, sensor 500 is engulfed by the bloodstream, forexample.

Once in place, the sensor may be located by various methods known in theart. For example, the presence and the intensity of Doppler shiftedsideband peaks in the frequency response of the sensor may be used toidentify or locate the sensor in the body and to assist the centering ofthe interrogating ultrasound beam on the sensor(s). The sensor reflectsthe carrier frequency ultrasound signal (with Doppler shift) with muchhigher amplitude than any tissue in the human body, thus theidentification and localization of the sensor and the centering of theinterrogating beam may be performed by searching for a significantDoppler effect in the received signal. If the interrogating beam isscanned across the region in which the sensor is implanted or located,the beam is centered on the sensor when the sideband frequency'samplitude is maximal. When correlating a received signal to a pulsecycle measurement, the pulsatile pressure changes the signal amplitudeof the Doppler sideband frequency (or frequencies) during the pulsecycle time. These pulsatile pressure induced sideband amplitude changesare present only in the signal reflected from the vibratable membranesof the sensor. Maximizing the amplitude of these pulsatile (periodic)amplitude changes may also be used by the system for sensoridentification and for beam centering. Thus, the operator or user of thedevice may scan the interrogating beam in the region where the implantedsensor is assumed to be positioned and look for the presence of asideband component (or components) at the expected frequency (orfrequencies) having an amplitude which periodically varies in time at arate similar to the blood pulse rate. In accordance with an embodimentof the invention, the pulsating sideband component may be visuallydetected on a display device coupled to the system. The interrogatingbeam may then be centered by carefully changing the beam directionand/or orientation in until the amplitude of the amplitude of theperiodically varying sideband is maximal.

The system's operator may then carefully scan the interrogating beamposition for fine-tuning the best beam position. The beam's position maybe fine-tuned or optimized by slowly changing the beam direction and/ororientation until the amplitude of the sideband peak(s) is themaximized. By maximizing the sideband amplitude the operator may ensurea good signal to noise ratio by maximizing the received energy at thesideband frequency or frequencies. Maximizing the amplitude of sidebandfrequency (or frequencies) may also contribute to improving thesignal-to-noise ratio and therefore the measurement accuracy and/or theinter-test and/or intra-test accuracy, repeatability and sensitivity.After beam centering, the operator may use the system for determiningthe blood pressure by determining the resonance frequency of thesensor(s) as disclosed in detail herein and computing the blood pressurefrom the determined resonance frequency (or frequencies).

It will be appreciated by persons having ordinary skill in the art thatmany variations, additions, modifications, and other applications may bemade to what has been particularly shown and described herein by way ofembodiments, without departing from the spirit or scope of theinvention. Therefore, it is intended that the scope of the invention, asdefined by the claims below, includes all foreseeable variations,additions, modifications, or applications.

What is claimed is:
 1. A vibratable sensor for measuring fluid pressure, the sensor device comprising: a chamber having at least one wall and a membrane, wherein the membrane forms one side of the chamber, and a bonding layer, said bonding layer and the membrane forming opposite walls of the chamber, wherein the membrane has a thickness of at least 1 micron, and the sensor has a total volume of less than or equal to 0.3 cubic millimeters.
 2. The sensor according to claim 1, wherein the membrane and said bonding layer are made of different materials.
 3. The sensor according to claim 1, wherein the bonding layer comprises a substance selected from glass and silicon.
 4. The sensor according to claim 1, wherein the bonding layer comprises glass.
 5. The sensor according to claim 1, wherein the bonding layer comprises PYREX.
 6. The sensor according to claim 1, wherein the sensor membrane comprises silicon, a metal, glass, or boron nitride.
 7. The sensor according to claim 1, wherein the sensor membrane comprises silicon or a silicon compound.
 8. The sensor according to claim 1, wherein the walls of the sensor are substantially perpendicular to the membrane.
 9. The sensor according to claim 1, wherein the chamber is sealed with a compressible gas of predefined pressure disposed therein. 